This invention relates to an improved amorphous form of cefpodoxime proxetil and a novel process for the production thereof.
Chemically, cefpodoxime proxetil is [(6R-[6xcex1,7xcex2(Z))]-7-{E(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid-1-[[(1-methylethoxy)carboxylic acid-1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester having the following formula 
and is covered in U.S. Pat. No. 4,486,425. Cefpodoxime Proxetil is a valuable antibiotic characterized by high broad spectrum activity against gram-positive and gram-negative micro-organisms. It has also been found to be highly active against susceptible and resistant strains of N. gonorrheae.
The latest trend in the pharmaceutical industry is to study polymorphism in drugs as well as the difference in the activity of different polymorphic forms of a given drug. The term polymorphism includes different physical forms, crystal forms, crystalline/liquid crystalline/non-crystalline (amorphous) forms. This has become very interesting especially after observing that many antibiotics, antibacterials, tranquilizers etc., exhibit polymorphism and one or more of the polymorphic forms of a given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymorphs. It has also been disclosed that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form [Konne T., Chem. Pharm. Bull., 38, 2003 (1990)]. For some therapeutic indications one bioavailability pattern may be favored over another. Sertraline, Frenitizole, Sulphathiazole, Indomethacine etc. are some of the important examples of pharmaceuticals which exhibit polymorphism. A host of patents have been granted pertaining to these drugs. To cite a few, U.S. Pat. No. 5,248,699 discusses about five polymorphic forms of sertraline hydrochloride while EP 014590 describes four polymorphic forms of Frentizole. EP 490648 and EP 022527 also deal with the subject of polymorphism in drugs.
Since cefpodoxime proxetil is poorly absorbed from the gastrointestinal tract, it is therefore present in sera and urine only in low concentrations after oral administration. Accordingly, there has been a need for a form of cefpodoxime proxetil which has better intrinsic dissolution and is capable of being better absorbed from the gastrointestinal tract following oral administration.
In accordance with the first aspect of the present invention, an efficient method is provided for the preparation of an amorphous form of cefpodoxime proxetil which has better intrinsic dissolution when compared with that of cefpodoxime proxetil prepared by conventional solvent precipitation.
The second aspect of the present invention provides a process for the preparation of cefpodoxime proxetil in an amorphous form which comprises dissolving cefpodoxime proxetil prepared by the conventional solvent precipitation in a suitable solvent followed by recovering amorphous form of cefpodoxime proxetil from the solution thereof by spray drying, wherein the amorphous form has a better intrinsic dissolution rate than cefpodoxime proxetil prepared by conventional solvent precipitation.
The term xe2x80x9csuitable solventxe2x80x9d is selected from the group consisting of ketones, alcohols, esters, chlorinated solvents, ethers, acetonitrile and mixtures thereof. Preferably, the solvent is selected from the group consisting of acetone, methanol, ethanol ethylacetate, chloroform, dichloromethane, tetrahydrofuran, 1,4-dioxan and mixtures thereof.
In accordance with the present invention cefpodoxime proxetil is recovered from the solution in an amorphous form using a spray drying technique. The Mini-Spray-Dryer (Model: Buchi 190, Switzerland) which is used, operates on the principle of nozzle spraying in parallel-flow i.e. the sprayed product and the drying gas flow in the same direction. The drying gas can be air or inert gases such as nitrogen, argon, and carbon dioxide. Nitrogen is preferred in this case.